Implications for service provision
The meta-analysis of effectiveness suggested that thromboprophylaxis in lower-limb immobilisation due to injury approximately halves the risk of any VTE and is associated with reductions in the risks of symptomatic DVT and PE. However, the evidence is limited to LMWH and fondaparinux, so it is unclear whether or not the findings can be extrapolated to DOACs. This in an important consideration as the absolute risks of clinically relevant VTE are low and patients may not be willing to submit to the inconvenience of parenteral treatment to reduce a relatively small risk.
The economic analysis suggested that thromboprophylaxis is effective and cost-effective compared with no thromboprophylaxis, so it would be reasonable to offer thromboprophylaxis to patients undergoing lower-limb immobilisation due to injury. This is based on the potential for thromboprophylaxis to reduce the risk of DVT and PE, with their long-term sequelae, rather than any meaningful reduction in the risk of mortality. The economic analysis also suggested that risk-based thromboprophylaxis using a RAM with a sensitivity of 84–89% and specificity of 46–55% is, potentially, the most cost-effective approach. This is similar to the prognostic accuracy of the L-TRiP(cast) score using a threshold score of 8 or 9, although estimates of sensitivity and specificity are very uncertain.
The cost-effectiveness of using an appropriate RAM is based on (1) reducing the number of people requiring thromboprophylaxis (and thus costs) compared with thromboprophylaxis for all, with only a small reduction in effectiveness and (2) increasing the number of VTE events prevented (and this effectiveness) compared with no thromboprophylaxis, with only a small increase in costs. Assuming universal acceptance by patients, a risk-based strategy, as outlined in the previous paragraph, would cost the English NHS £6M per year and gain 891 QALYs compared with no thromboprophylaxis. Compared with this, providing thromboprophylaxis for all would cost an additional £8.2M per year and gain an additional 160 QALYs. These estimates are not intended to be precise figures, as strategies are unlikely to be implemented perfectly and patients may decline treatment, but they provide an indication of the potential implications of different strategies for service provision.
The PPI representatives highlighted the importance of patient involvement in decision-making and the need for clear and comprehensible information to be provided. This has important implications for service provision. To participate in shared decision-making, patients need to understand that the risk of clinically important VTE is relatively low but that it can be reduced by thromboprophylaxis. The effectiveness of thromboprophylaxis relies on the benefits of reducing DVT and PE (and their sequelae), outweighing a small increase in the risk of bleeding, but VTE events may still occur despite thromboprophylaxis. The risks of death from VTE or bleeding after immobilisation due to injury are very small regardless of the treatment strategy, and thromboprophylaxis is unlikely to have any significant impact on the risk of death.
Suggested research priorities
This analysis suggested that risk-based thromboprophylaxis using a RAM with sensitivity of 84–89% and specificity of 46–55% would be the most cost-effective strategy. However, the current evidence base for RAMs is very limited and estimates of sensitivity and specificity are subject to substantial uncertainty. Improving the evidence base for RAMs is therefore a key priority.
Ideally, a large prognostic cohort study of people experiencing lower-limb immobilisation due to injury would be undertaken to estimate the prognostic accuracy of existing RAMs for VTE and possibly derive a new RAM. However, the evidence of effectiveness and cost-effectiveness provided by this analysis suggests that thromboprophylaxis should be offered to patients in this cohort, or at least those considered as being at a higher risk. Administration of thromboprophylaxis would be expected to reduce the risk of VTE and thus lead to underestimation of the prognostic accuracy of RAMs. Furthermore, the VTE events that were prevented by thromboprophylaxis would be precisely those that we would want a RAM to predict.
A large cohort study could still provide useful information if it is used to evaluate implementation rather than accuracy. It could determine the proportion of the cohort receiving thromboprophylaxis with different RAMs or different thresholds for treatment. It could be used to determine whether or not the low rate of bleeding events is confirmed in practice and, if risk-based thromboprophylaxis were provided, it could be used to determine whether or not the low rate of VTE events is confirmed in low-risk patients who do not receive treatment.
Direct oral anticoagulants could provide the benefits of thromboprophylaxis without the costs, inconvenience and discomfort of injections, which the PPI representatives identified as a potential barrier to patient acceptance. However, all the evidence of effectiveness in this review related to LMWH or fondaparinux. Ideally, an appropriately powered RCT comparing thromboprophylaxis of DOACs with LMWH would provide evidence of equivalent effectiveness, but such a trial may be prohibitively expensive, especially if it were felt that evidence of effectiveness of DOAC for other indications could be reasonably extrapolated to lower-limb immobilisation.
The most important parameters for decision uncertainty in the value-of-information analysis were related to the efficacy and disutility of receiving prophylaxis, and the long-term complications of PTS, so estimating these parameters should be a priority for future research. The disutility of receiving LMWH injections or oral DOACs could be investigated as part of a cohort study or trial of different types of thromboprophylaxis. The uncertainty around the long-terms effects of PTS mainly relate to subclinical DVT rather than clinically detected and treated DVT, so research to reduce uncertainty around the incidence and disutility of PTS would need to involve long-term follow-up or a retrospective observational study of people following lower-limb immobilisation due to injury.
It is currently unclear whether or not people with limited lower-limb immobilisation (such as splints that allow some movement or removable splints or casts) carry similar risks of VTE to those with full immobilisation. A cohort study of this population, perhaps undertaken alongside a cohort study evaluating risk-based thromboprophylaxis, could determine the risk of VTE and identify risk predictors.
All of these research suggestions would require large numbers of participants to generate meaningful results. There are plenty of eligible participants presenting to the NHS but an efficient research design would be required, using standardised collection of predictor variables and routine data sources for outcomes, to ensure that any study was not prohibitively expensive.
Finally, the PPI representatives identified the need for patients to receive clear and comprehensible communication of the risks and benefits of thromboprophylaxis, including written materials. Research is required to develop information for patients and ways of communicating benefits and risks.
